Remediation of Superfund sites involves either containment or destruction of the chemicals, frequently by on-site thermal treatment or off-site incineration. Combustion by-products include a mixture of (1) particles of fly-ash and soot, (2) a wide variety of gas-phase organic chemicals, (3) organic chemicals physisorbed to particles, and (4) persistent free radicals (PFRs) formed by chemisorption of some chemicals to transitionmetal- containing particles. The emitted particles are primarily fine and ultra-fine particulate (UFP). These fractions, but especially the UFP fractions, are capable of penetrating deep into the lung, and accessing the systemic circulation, which have been shown to cause cardiac toxicity, pulmonary toxicity, and genotoxicity. Despite the ubiquitous exposure of humans to UFP, very little is known about the mechanisms of toxicity from these substances. The toxic responses have been reported to be mediated through the generation of reactive oxygen species (ROS), with several studies implicating the P450 system in this process. The goal of this project is to examine the role of cytochrome P450 in the bioactivation of PFR containing UFPs, and to identify the components of UFPs responsible for its modulation. Tailor-made, laboratory-generated UFP surrogate systems will be generated by our chemical colleagues to test specific mechanistic hypotheses. The specific aims include: Aim #1 - Examination of the ability of PFR/UFP systems to modulate P450 function in lung and heart. These studies will focus on whether P450 enzyme levels are affected by prior exposure to UFP, and will be examined both in healthy rats and those with chronic obstructive pulmonary disease. Aim #2 - Examination of the disposition of UFP and identification of the metabolites produced. In these studies, we will examine the ability of laboratory-generated PFR/UFP sytems to be metabolized by the cytochrome P450 enzyme system and to identify the primary metabolites produced. Aim #3 - Examination of the role of PFR/UFP systems to modulate intracellular reactive oxygen species generation through the P450 system. Taken together, these experiments not only will be used to identify the P450 forms that are affected by UFPs, but will also determine which component(s) of UFPs are responsible for these effects. Furthermore, these studies will help to identify the enzymes that mediate bioactivation of PFR/UFP systems to their toxic forms.